This project's goal is develop new drugs that repair synaptic connections and restore normal communication between neurons in the brain to provide better treatments for Alzheimers disease (AD) and other tauopathies. During this period, the project team completed a qHTS screen, as well as a virtual screen, for caspase-2 inhibitors. Following completion of both screens, active compounds were characterized by counter-screen, further profiled and triaged. The activity of purified powders for the most promising hits were validated. The hits with validated activity were further tested for their ability to aggregate or form covalent adducts. The top compounds will be advanced to hit-to-lead probe development to develop an inhibitor for advanced mouse models of Alzheimers disease.